Useful Links for the Medical Community
Medical and Research Papers
This section covers interesting research on Rh disease as well as an overview of the current world situation.
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Citation:
Heydarchi B, D’Silva DB, Wong H, Goddard-Borger ED, Wicks IP. Fc mutagenesis enhances the functionality of anti-RhD monoclonal antibodies. Blood Advances. 2025 Apr 8;9(7):1522-33.
Summary:
Commercially-available polyclonal anti-RhD immunoglobulin G (RhD-pIgG) provides effective immunoprophylaxis to prevent maternal sensitization to RhD, thereby preventing Rh disease; nonetheless, its use is primarily restricted to high-income countries. In addition, there are currently global shortages of RhD-pIgG. Therefore, monoclonal antibodies (mAbs) offer a promising alternative, although there are currently significant questions about their efficacy in this regard. Appropriate glycosylation of antibody Fc regions is important for modulating antibody-dependent cellular cytotoxicity (ADCC) activity, which also seems to be relevant for the efficacy of RhD-pIgG. In this paper, the Fc regions of two anti-RhD mAbs were genetically modified to enhance ADCC activity, which compared favorably to that provided by RhD-pIgG. Thus, this may offer a promising approach to developing clinically-effective anti-RhD mAbs.
Weblink:
Free download: https://ashpublications.org/bloodadvances/article-pdf/9/7/1522/2362715/blooda_adv-2024-015082-main.pdf
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Citation:
Pell LG, Ariff S, Nawaz Khan G, Dampf H, Muhammad Jokhio S, Zipursky A, Baker JM, Nausheen S, Soofi S, Morris SK. (2025) Point-of-care determination of the frequency of Rhesus(D)-negative blood types and the uptake of anti(D) immunoglobulin among Rh(D)-negative women in Dadu district, Sindh, Pakistan. PLOS Glob Public Health 5(4): e0004395.
Summary:
To prevent Rh disease in rural Pakistan, this study evaluated the ability of lady health visitors to perform point-of-care testing to identify of RhD-negative pregnant women and then administer two doses of Rh immune globulin (i.e., at 28-weeks gestation and immediately post-partum). The prevalence of RhD-negativity was high in this population (i.e., 17%), and 91% and 96% of these patients received their first and second dose of Rh immune globulin, respectively. At the beginning of the study, the patients had little knowledge about Rh disease and understanding among lady health visitors varied greatly; however, knowledge increased dramatically among all of these individuals as a result of their study participation. One limitation of the study is that only 21% of the pregnant women were primagravidas; therefore, multiple participants may have already been sensitized to RhD. Nonetheless, this study demonstrates that it is feasible to screen for RhD-negativity and provide appropriate immunoprophylaxis to prevent Rh disease, even in a rural area of Pakistan, by educating pregnant women and by training and engaging local, non-physician health care providers.
Weblink:
Free download: https://doi.org/10.1371/journal.pgph.0004395
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Citation:
Ding JC, Montemayor-Garcia C, Stotler BA, Spitalnik SL, Méndez JA. Rh disease in Mexico: evaluating regional and institutional differences in treatment availability and disease management: Rh disease awareness in Mexico. Blood Transfusion. 2025;23(2):109-17. PMID: 391336 PMCID: PMC11925255 DOI: 10.2450/BloodTransfus.750
Summary:
A significant burden of Rh disease still exists in Mexico. To examine disparities in the allocation of maternal and child health resources, as well as clinical knowledge regarding Rh disease, a questionnaire was sent to all Mexican obstetricians-gynecologists. Significant regional variations in prevention and treatment were found, particularly with regard to providing anti-RhD immunoglobulin to prevent alloimmunization. Closing the gap in the availability of anti-RhD immunoglobulin should take priority in future efforts aimed at providing equitable care, because this will yield the preferred outcome of preventing Rh disease, rather than needing to use more complex measures to treat Rh disease after it develops. These results can inform strategies to understand and eliminate these healthcare disparities.
Weblink:
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Abstracts in PDF.
Citation:
Ling, L.E., Hillson, J.L., Tiessen, R.G., Bosje, T., van Iersel, M.P., Nix, D.J., Markowitz, L., Cilfone, N.A., Duffner, J., Streisand, J.B., Manning, A.M. and Arroyo, S. (2019), M281, an Anti‐FcRn Antibody: Pharmacodynamics, Pharmacokinetics, and Safety Across the Full Range of IgG Reduction in a First‐in‐Human Study. Clin. Pharmacol. Ther., 105: 1031-1039. doi: 10.1002/cpt.1276. Epub 2018 Dec 4. PMID: 30402880; PMCID: PMC6587432.
Summary:
Previous work showed that endothelial cell expression of FcRn, the neonatal Fc receptor, prevents the intracellular degradation of IgG, thereby extending its circulatory half-life. This led to the development of M281, an anti-FcRn monoclonal antibody, which, in ex-vivo experiments, produced a transient and global increase in IgG clearance and reduced trans-placental IgG transmission. The current paper describes the first-in-human Phase I trial of M281 in 50 healthy subjects, in which they found an ~85% reduction in circulating IgG in the multiple dose arm, no effects on non-IgG antibody levels, and a similar incidence of adverse events in both the placebo and treatment groups. Although these initial results are very promising, due to the limited size of the study in otherwise healthy research subjects, further safety profiling, especially in pregnant mothers, fetuses, and immunocompromised patients, remains necessary.
Weblink:
Citation:
Baker JM, Campbell DM, Pavenski K, Gnanalingam A, Hollamby K, Jegathesan T, Zipursky A, Bhutani V, Sgro M; NeoHBC. Infants affected by Rh sensitization: A 2-year Canadian National Surveillance Study. Paediatr Child Health. 2020 Mar 30;26(3):159-165. doi: 10.1093/pch/pxaa025. PMID: 33936335; PMCID: PMC8077204.
Summary:
Although the number of cases of Rh disease in the US, Canada, and Western Europe remain relatively low, it remains important to characterize the disease in these settings. Utilizing an extensive survey of pediatricians throughout Canada, this paper identified 62 cases of Rh disease between 2016 and 2018. Demographics, lab values, and treatment outcomes were assessed in detail, identifying an occurrence of Rh disease of ~8 out of every 100,000 births in Canada. Of note, almost 25% of Canadian cases occurred in immigrant mothers, highlighting the need for increased global prophylactic and education measures. Additionally, they noted that this number is likely an underestimate, given the 85% response rate, exclusive survey of pediatricians only, lack of miscarriage data, and the possibility of unrecognized cases.
Weblink:
Citation:
Escamilla-Rivera V, Santhanakrishnan M, Liu J, Gibb DR, Forsmo JE, Foxman EF, Eisenbarth SC, Luckey CJ, Zimring JC, Hudson KE, Stowell SR, Hendrickson JE. Complement Plays a Critical Role in Inflammation-Induced Immunoprophylaxis Failure in Mice. Front Immunol. 2021 Jun 25;12:704072. doi: 10.3389/fimmu.2021.704072. PMID: 34249009; PMCID: PMC8270673.
Summary:
Polyclonal anti-KEL immunoglobulin has been demonstrated to prevent alloimmunization. However, breakthrough cases can occur when the recipient is in a state of viral-like inflammation. Escamilla-Rivera et al (2021) examine the mechanism for this failure. In a murine model, they demonstrate a “two-hit” model in which complement (C3 and C1q) and complement receptors (CR1 and CR2) are required for alloantibody production in the setting of anti-KEL immunoglobulin and a virus-like stimulus. This may have translational relevance to immunoprophylaxis failure with anti-Rh(D) immunoglobulin.
Link (free access):
https://www.frontiersin.org/articles/10.3389/fimmu.2021.704072/full
Citation:
Alshehri AA, Jackson DE. Non-Invasive Prenatal Fetal Blood Group Genotype and Its Application in the Management of Hemolytic Disease of Fetus and Newborn: Systematic Review and Meta-Analysis. Transfus Med Rev. 2021 Apr;35(2):85-94. doi: 10.1016/j.tmrv.2021.02.001. Epub 2021 Mar 1. PMID: 33781630.
Summary:
Non-Invasive Prenatal Testing (NIPT) has the potential to identify pregnancies at risk of developing Hemolytic Disease of the Fetus and Newborn (HFDN) by genotyping fetal RHD exons. In the absence of fetal RHD antigens, NIPT can reduce unnecessary anti-Rh(D) prophylaxis. Alshehri and Jackson (2021) find that RHD genotyping with NIPT can be highly sensitive and specific (99% and 98% at the 95% confidence level, respectively) under appropriate conditions.
NCBI Link (not free access):
Citation:
Yu M, Tang T, Zheng R, Situ M, Feng J. A comparative study on perinatal outcomes of red blood cell-alloimmunized pregnancies with anti-RhD in combination and anti-RhD alone in China. Vox Sang. 2022 Feb;117(2):268-274. doi: 10.1111/vox.13161. Epub 2021 Jun 10. PMID: 34111300.
Summary:
In a retrospective, single-center study of 165 alloimmunized women in Guangzhou, China, Yu et al. (2020) examined whether perinatal outcomes differed between pregnancies alloimmunized with anti-RhD (n=133) alone versus anti-RhD in combination with anti-RhC or anti-RhE (n=32). Fetuses of combination pregnancies were significantly more likely to be anemic and require intrauterine transfusions than fetuses of anti-RhD only pregnancies. Fetuses of combination pregnancies were also more likely to require simple transfusions, but there was no difference observed for exchange transfusions. This study suggests that fetuses of mothers with both anti-Rh antibodies and antibodies against other Rh-family antigens may be at increased risk of requiring intrauterine and simple transfusions.
NCBI Link (not free access):
Hemolytic disease of the fetus and newborn due to Rh(D) incompatibility: A preventable disease that still produces significant morbidity and mortality in children
Valeria Pegoraro, Ducciocompet Urbinati, Gerard H. A. Visser, Gian Carlo Di Renzo, Alvin Zipursky, Brie A. Stotler, Steven L. Spitalnik
This interesting study brings to light the fact that even though anti-Rh(D) has been given regulatory approval in 1968, around 50% of women around the world still don’t have access to this immunoprophylaxis.
Provider guidelines
We are compiling a list of useful guidelines for care providers.
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This comprehensive guideline gives information about Rh disease, its causes, symptoms, diagnosis and treatment/management.
Useful Links for Rh-negative Women and Families
If you are considering a pregnancy or are already pregnant, here is a list of useful and accessible information and links.
Promotional Material
You will find some useful WIRhE visuals should you wish to promote our initiatives in your region of the world.
Video
Here are some engaging videos to discover more about the Rh disease, Rh disease eradication projects around the world and the WIRhE initiative.
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Steven Spitalnik, MD and Executive Director of WIRhE gives a talk about the Rh disease’s heavy toll in the world today and the reasons why the WIRhE consortium was created. This talk was given at the South Central Association of Blood Banks on August 28, 2020.
View on Youtube